Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. Recently, a series of 5-substituted pyrrolo[2,3-d]pyrimidine compounds of formula XVI: ##STR3## where R is NHC*H(CO.sub.2 R.sup.1)CH.sub.2 CH.sub.2 CO.sub.2 R.sup.1 or OR.sup.1, the configuration about the carbon atom designated * is L, each R.sup.1 is hydrogen or the same or different carboxy protecting group, m is 2 or 3, and A is an aryl group; and their pharmaceutically acceptable salts were disclosed as antifolates or intermediates to antifolates. U.S. Pat. No. 5,416,211 (U.S. '211).
A key intermediate to compounds of formula XVI is the .alpha.-halo aldehyde of formula XV: ##STR4##
Among the possible routes to compounds of formula XV disclosed in U.S. '211, alpha halogenation of aldehydes of formula XIV: ##STR5## is most direct.
A synthesis published by Taylor and Harrington teaches the route to compounds of formula XIV shown below: ##STR6## Taylor, E. C., Harrington, P. M., J.Org.Chem., 55, 3222, (1990).
Another synthesis published by Larock, et. al., may be used to form the requisite aldehydes of formula XIV by a similar palladium[0] catalyzed coupling shown below: ##STR7## Larock, R. C., Leung, W., Stolz-Dunn, S., Tet.Let., 30, 6629, (1989).
If the procedure of Larock is followed, a mixture of desired and undesired products results, the components of which are very difficult to separate and purify to afford compounds of formula XIV. In addition, regardless of how they are formed, aldehydes of formula XIV are typically not isolated, due to their inherent instability, and are instead alpha halogenated in situ to provide the alpha halo aldehydes of formula XIX, as disclosed in U.S. '211.
An improvement over the prior art would provide a facile method for selectively producing a compound of formula XIV and would provide an aldehyde analogue amenable to isolation, bulk manufacturing, and storage easily convertible to it's aldehyde form.